Beta-hydroxybutyrate mixed salt compositions and methods of use

ABSTRACT

Ketogenic compositions including a plurality of beta-hydroxybutyrate (BHB) salts are formulated to induce or sustain ketosis in a subject to which the ketogenic compositions are administered. The BHB mixed salt is formulated to provide a biologically balanced set of cationic electrolytes and avoid detrimental health effects associated with imbalanced electrolyte ratios. A ketogenic composition includes BHB salts selected from sodium, potassium, calcium, and magnesium salts. The BHB composition may also include transition metal cations (e.g., zinc or iron), one or more BHB-amino acid salts, a short-, medium-, or long-chain fatty acid source, vitamins, minerals, flavorants, or other excipients.

CROSS-REFERENCE TO RELATED APPLICATIONS

This Application is a continuation of U.S. patent application Ser. No.16/720,211, filed Dec. 19, 2019, which is a division of U.S. patentapplication Ser. No. 16/272,145, filed Feb. 11, 2019, now U.S. Pat. No.10,736,861, which is a continuation-in-part of U.S. patent applicationSer. No. 15/454,157, filed Mar. 9, 2017, now U.S. Pat. No. 10,292,952,which claims the benefit of U.S. Provisional Patent Application No.62/307,203, filed Mar. 11, 2016, which are incorporated herein byreference in their entirety. This application is also a continuation ofU.S. patent application Ser. No. 16/996,509, filed Aug. 18, 2020, whichis incorporated by reference in its entirety.

BACKGROUND 1. Field of Disclosure

This disclosure relates to the use of exogenous ketones and ketogenicprecursors to quickly produce elevated and sustained levels of ketonebodies in the blood and methods for assisting the body's transition intonutritional ketosis. Specifically, compositions and methods aredisclosed which promote, enhance, and/or sustain ketosis in a mammalwithout contributing to or aggravating an electrolyte imbalance, and inat least some circumstances, helping to restore electrolyte balance.

2. Related Technology

In periods of fasting, extreme exercise, and/or low carbohydrateconsumption, glucose and glycogen stores in the body are rapidly usedand can become quickly depleted. Failure to replenish glucose stores asthey become depleted causes the body to metabolically shift to thecreation of ketone bodies for energy. Ketone bodies can be used byalmost all cells of the body as a replacement fuel to satisfy the body'senergy needs, including the needs of the brain and heart. During aprolonged fast, for example, blood ketone levels will increase to ashigh as 2 or 3 mmol/L or more. It is conventionally understood that whenblood ketones rise above 0.5 mmol/L, the heart, brain and peripheraltissues are using ketone bodies (beta-hydroxybutyrate and acetoacetate)as the primary fuel source. This condition is referred to as ketosis, orbetween 1.0 mmol/L and 3.0 mmol/L is called “nutritional ketosis.”

Upon transitioning into ketosis, or in other words, during ketogenicmetabolism in the liver, the body uses dietary and bodily fats as itsprimary energy source. Consequently, once in ketosis, one can induceloss of body fat by controlling dietary fat intake and adjustingcarbohydrate intake low enough to sustain ketosis.

While in ketosis, the body is in ketogenisis and essentially burning fatfor its primary fuel. The body begins cleaving fats into fatty acids andglycerol and transforms the fatty acids into acetyl CoA molecules, whichare then eventually transformed through ketogenisis into the watersoluble ketone bodies beta-hydroxybutyrate (β-hydroxybutyrate or “BHB”),acetoacetate (also known as acetylacetonate), and acetone in the liver.Beta-hydroxybutyrate and acetoacetate are the ketone bodies used by thebody for energy while acetone is removed as a by-product of ketogenesis.

The metabolism of ketone bodies is also associated with other beneficialeffects, including anticonvulsant effects, enhanced brain metabolism,ncuroprotection, muscle sparing properties, and improved cognitive andphysical performance. Science-based improvements in efficiency ofcellular metabolism, managed through ketone supplementation, can havebeneficial impacts on physical, cognitive health, psychological health,and a long-term impact on health with respect to the common avoidablediseases such as obesity, cardiovascular disease, neurodegenerativediseases, diabetes, and cancer.

Despite the many health advantages to pursuing a ketogenic diet orlifestyle and maintaining a state of nutritional ketosis, there remainsignificant barriers to pursuing and maintaining a ketogenic state. Oneof these barriers is the difficulty of transitioning into a ketogenicstate. The fastest endogenous way to entering ketosis through depletingglucose stores in the body is through fasting combined with exercise.This is physically and emotionally demanding and is extremelychallenging even for the most motivated and disciplined.

Additionally, the transition into ketosis is often accompanied byhypoglycemia which can cause lethargy and light-headedness in many,resulting in an uncomfortable physiological and mental state commonlyreferred to as the “low-carb flu.” In addition, many people experience adown regulation in their metabolism as the body goes into an“energy-saving” mode. Some suggest that these transitory symptoms maylast as long as two to three weeks During this transition period, if anymeal or snack consisting of carbohydrates over the restrictive amount isconsumed, there is an immediate termination of ketogenisis exiting thebody from its state of ketosis as the body shifts back to glucoseutilization for its primary fuel and the transition into ketosis mustbegin anew.

If a subject is successful in establishing ketosis, the act ofsustaining ketosis is likewise if not a more difficult challenge due tothe need to maintain a rigid dietary ratio of carbohydrates and proteinto fats. It is further complicated by the disruption of normalelectrolyte balances that often occurs when transitioning into andmaintaining a ketogenic state. The depletion and lowering of glycogenstores in the liver and muscles lessens the ability of the body toretain water, leading to more frequent urination, and accordingly, agreater loss of electrolytes. Further, the drop in insulin levels causedby ketosis effects the rate at which certain electrolytes are extractedby the kidneys, additionally lowering electrolyte levels in the body.

Such electrolyte imbalances can lead to fatigue, muscle cramping,headaches, dizziness, depression, constipation, skin problems, muscleweakness, and irritability, exacerbating the other detrimental mentaland physiological effects often associated with entering and maintaininga ketogenic state, and further increasing the difficulty of promotingand/or sustaining ketosis.

In addition, in more extreme cases, electrolyte imbalances can lead tovery serious health problems, such as heart palpitations, respiratorydepression, involuntary muscle spasms, and cardiac arrhythmia.

Accordingly, there is a long felt and continuing need for compositionsand methods for promoting and/or sustaining ketosis without causing oraggravating detrimental effects associated with ketosis.

BRIEF SUMMARY

Certain embodiments disclosed herein are directed to ketogeniccompositions formulated for inducing and/or sustaining ketosis in asubject while simultaneously promoting or maintaining a beneficialelectrolytic balance. For example, one or more ketogenic compositionsdescribed herein may function to induce and/or sustain ketosis in thesubject to which the composition is administered without delivering toomuch total electrolyte to the body, or too much of a particularelectrolyte that may be unhealthy, such as sodium and/or calcium (i.e.,so as to not exceed the RDA for a particular electrolyte or only exceedit by a predetermined amount). This allows the ketogenic compositions toinduce or sustain ketosis while simultaneously limiting, preventing, orimproving an electrolyte imbalance in the subject.

In some embodiments, a ketogenic composition for promoting and/orsustaining ketosis in a subject includes a beta-hydroxybutyrate((3-hydroxybutyrate or “BHB”) mixed salt formed from at least fourdifferent cations and comprising 10-70% by weight of sodium BHB, 10-70%by weight of potassium BHB, 10-70% by weight of calcium BHB, and 10-70%by weight of magnesium BHB. Other cations, such as cations provided byorganic compounds, such as amines or amino acids, can form compounds orcomplexes with BHB. Using organic cations permits higher dosing of BHBwithout causing electrolyte imbalances or overload.

In some embodiments, a ketogenic composition for promoting and/orsustaining ketosis in a subject includes a plurality of salts formulatedfrom at least four different cations and a single anion, wherein thesingle anion is BHB, and wherein other anions are omitted from theplurality of salts, the cations being formulated so as to provide abiologically balanced set of cationic electrolytes upon administrationto the subject.

In some embodiments, a ketogenic composition for promoting and/orsustaining ketosis in a subject includes: a potassium BHB salt; a sodiumBHB salt included in an amount, by weight, that is no greater than anamount, by weight, of the potassium BHB salt; a magnesium BHB salt; anda calcium BHB salt included in an amount, by weight, that is no greaterthan an amount, by weight, of the magnesium BHB salt.

Some embodiments additionally include one or more transition metal BHBsalts, such as zinc BHB or iron BHB. They may also include BHB-aminoacid salts.

By limiting the total quantity of sodium and/or calcium BHB salts or anyother total quantity of single cationic electrolytes or metal or aminoacids in the ketogenic composition (e.g., by including higher amounts ofpotassium BHB, magnesium BHB, one or more transition metal BHB salts,and/or one or more BHB-amino acid salts), it is possible tosubstantially increase the total quantity of BHB delivered to the bodywithout delivering an excessive or unhealthy quantity of cationicelectrolytes or metal or amino acids (e.g., sodium and/or calciumcations to the body).

The BHB compound can be provided as a racemic mixture of enantiomers, orDL-beta hydroxybutyrate, which can be made synthetically. In humans, theenantiomer D-3-hydroxybutyrate (“D-beta hydrobutyrate” or “D-BHB”) issynthesized in the liver from acetoacetate, the first ketone produced inthe fasting. Therefore, it may be desirable to provide BHB as theenantiomer D-3-hydroxybutyrate to increase potency, either enrichedrelative to L-3-hydroxybutyrate (“L-beta hydrobutyrate” or “L-BHB”) orisolated from L-3-hydroxybutyrate. D-3-hydroxybutyrate is also referredto as “R-beta-hydroxybutyrate”.

Some embodiments additionally include a nutritionally acceptable amountof vitamin D₃. For example, a composition may include vitamin D₃ suchthat a daily dosage amount of the composition includes vitamin D₃ in anamount ranging from about 200 IU to about 8000 IU, or about 400 IU toabout 4000 IU, or about 600 IU to about 3000 IU.

In some embodiments, a ketogenic composition is useful as a weight losssupplement, as a treatment for high blood glucose or type II diabetes,as a brain tonic, athletic performance enhancer, as a preventativeagainst metabolic dysfunction, mitochondrial defect, insulin resistance,as an adjunct to a ketogenic diet, as an anti-aging supplement, and forother uses associated with improved metabolic health.

In preferred embodiments, the ketogenic composition is provided as asolid or powder form as opposed to a liquid or gel form. Such solid-formketogenic compositions, in addition to providing the beneficialketogenic effects and beneficial electrolytic effects described herein,are preferably also formulated so as to provide for sufficient ease ofhandling and manufacturability. Alternatively, the composition may be inthe form of a liquid mouth spray for fast delivery and uptake. In someembodiments, the beneficial ketogenic and electrolytic effects arerealized without hampering or overly impacting the manufacturability orease of handling of the composition.

Additional features and advantages will be set forth in part in thedescription that follows, and in part will be obvious from thedescription, or may be learned by practice of the embodiments disclosedherein. It is to be understood that both the foregoing brief summary andthe following detailed description are exemplary and explanatory onlyand are not restrictive of the embodiments disclosed herein or asclaimed.

DETAILED DESCRIPTION I. Definitions

The compound “beta-hydroxybutyrate,” also known as β-hydroxybutyrate,3-hydroxybutyrate, pHB, BHB, or beta-hydroxybutyrate, is thedeprotonated form of beta-hydroxybutyric acid, which is ahydroxycarboxylic acid having the general formula CH₃CH₂OHCH₂COOH. Thedeprotonated form present at typical biological pH levels isCH₃CH₂OHCH₂COO⁻. The general chemical structure shown below representsbeta-hydroxybutyrate compounds that may be utilized in the disclosedcompositions:

where,

X can be hydrogen, metal ion, amino cation such as from an amino acid,alkyl, alkenyl, aryl, or acyl.

When X is a hydrogen, the compound is beta-hydroxybutyric acid. When Xis a metal ion or an amino cation, the compounds is abeta-hydroxybutyrate salt. When X is alkyl, alkenyl, aryl, or acyl, thecompounds is a beta-hydroxybutyrate ester. The foregoing compounds canbe in any desired physical form, such as crystalline, powder, solid,liquid, solution, suspension, or gel.

Unless otherwise specified, the term “salt” does not mean or imply anyparticular physical state, such as a crystalline, powder, other solidform, dissolved in water to form a liquid solution, dispersed in aliquid to form a suspension, or gel. A salt can be formed in solution,such as by at least partially neutralizing beta-hydroxybutyric acid witha strong or weak base, such as an alkali or alkaline earth metalhydroxide, carbonate, or bicarbonate, basic amino acid, and the like.

Beta-hydroxybutyrate can be utilized by a patient's body as a fuelsource during instances of low glucose levels in the subject or when apatient's body is supplemented with a usable form ofbeta-hydroxybutyrate. Beta-hydroxybutyrate is commonly referred to as a“ketone body” although not technically a ketone.

As used herein, “ketogenic composition” refers to a compositionincluding a mixed BHB salt. The ketogenic composition is formulated toinduce and/or sustain ketosis in a subject to which it is administeredwhile simultaneously promoting electrolytic benefits in the subject.

The term “mixed salt” or “multi-salt” is used herein to describe theportion of a ketogenic composition comprising the multiple BHB salts.The mixed BHB salts include at least four separate cation forms of BHBsalt, and the salts are relatively proportioned to promote electrolyticbenefits in the subject.

As used herein, “subject” or “patient” refers to members of the animalkingdom, including mammals, such as but not limited to, humans and otherprimates; rodents, fish, reptiles, and birds. The subject may be anyanimal requiring therapy, treatment, or prophylaxis, or any animalsuspected of requiring therapy, treatment, or prophylaxis. Prophylaxismeans that regiment is undertaken to prevent a possible occurrence, suchas where a high glucose or diabetes is identified. “Patient” and“subject” are used interchangeably herein.

The term “unit dose” refers to a dosage form that is configured todeliver a specified quantity or dose of composition or componentthereof. Example dosage forms include, but are not limited to, tablets,capsules, powders, food products, food additives, beverages, beverageadditives, candies, suckers, pastilles, food supplements, sprays,injectables, and suppositories. Such dosage forms may be configured toprovide a full unit dose or fraction thereof (e.g., ½, ⅓, or ¼ of a unitdose).

Another dosage form that can be used to provide a unit dose ofcomposition or component thereof is a unit dose measuring device, suchas a cup, scoop, syringe, dropper, spoon, or colonic irrigation device,which is configured to hold therein a measured quantity of compositionequaling a full unit dose or fraction thereof (e.g., ½, ⅓, or ¼ of aunit dose). For example, a bulk container, such as a carton, box, can,jar, bag, pouch, bottle, jug, or keg, containing several unit doses ofcomposition (e.g., 5-250 or 10-150 unit doses) can be provided to a usertogether with a unit dose measuring device that is configured to providea unit dose, or fraction thereof, of composition or component thereof.

A kit for use in providing a composition as disclosed herein in bulkform, while providing unit doses of the composition, may comprise a bulkcontainer holding therein a quantity of composition and a unit dosemeasuring device configured to provide a unit dose, or fraction thereof,of composition or component thereof. One or more unit dose measuringdevices may be positioned inside the bulk container at the time of sale,attached to the outside of the bulk container, prepackaged with the bulkcontainer within a larger package, or provided by the seller ormanufacture for use with one or multiple bulk containers.

The kit may include instructions regarding the size of the unit dose, orfraction thereof, and the manner and frequency of administration. Theinstructions may be provided on the bulk container, prepackaged with thebulk container, placed on packaging material sold with the bulkcontainer, or otherwise provided by the seller or manufacturer (e.g., onwebsites, mailers, flyers, product literature, etc.) The instructionsfor use may include a reference on how to use the unit dose measuringdevice to properly deliver a unit dose or fraction thereof. Theinstructions may additionally or alternatively include a reference tocommon unit dose measuring devices, such as spoons, spatulas, cups, andthe like, not provided with the bulk container (e.g., in case theprovided unit dose measuring device is lost or misplaced). In such case,a kit may be constructed by the end user when following instructionsprovided on or with the bulk container, or otherwise provided by theseller regarding the product and how to properly deliver a unit dose ofcomposition, or fraction thereof.

“Ketosis” as used herein refers to a subject having blood ketone levelswithin the range of about 0.5 mmol/L and about 16 mmol/L in a subject.Ketosis may improve mitochondrial function, decrease reactive oxygenspecies production, reduce inflammation and increase the activity ofneurotrophic factors. “Keto-adaptation” as used herein refers toprolonged nutritional ketosis (>1 week) to achieve a sustainednonpathological “mild ketosis” or “therapeutic ketosis.”

The term “medium chain triglycerides” (MCT) refers to molecules having aglycerol backbone attached to three medium chain fatty acids. Mediumchain fatty acids range from 6 to 12 carbon atoms in length, e.g., 8 to10 carbon atoms in length. Exemplary fatty acids are caprylic acid, alsoknown as octanoic acid, comprising 8 carbon molecules, and capric acid,also known as decanoic acid, comprising 10 carbon molecules. BecauseMCTs are ketone body precursors, including one or more MCTs may providean additional source for the production of ketone bodies independent ofthe BHB-salts, thus helping to mitigate the risk of consuming too manyelectrolytes in elevating ketone levels to a desired therapeutic level.

In addition, the composition may comprise at least one short chain fattyacid, or a mono-, di- or triglyceride, or other ester of the at leastone short chain fatty acid, having fewer than 6 carbons and/or at leastone long chain fatty acid, or a mono-, di- or triglyceride of the atleast one long chain fatty acid, having more than 12 carbons

Examples of short chain fatty acids include acetic acid, propionic acid,butyric acid, isobutyric acid, valeric acid, and isovaleric acid.Examples of medium chain fatty acids include caproic acid, caprylicacid, capric acid, and lauric acid. Examples of long-chain fatty acidsinclude myristic acid, palmitic acid, stearic acid, arachidic acid,behenic acid, lignoceric acid, cerotic acid, omega-3 fatty acids,omega-6 fatty acids, omega-7 fatty acids, and omega-9 fatty acids.

The term “administration” or “administering” is used herein to describethe process in which the mixed salt ketogenic compositions are deliveredto a subject. The composition may be administered in various waysincluding oral, intragastric, and parenteral (referring to intravenousand intra-arterial and other appropriate parenteral routes), amongothers.

II. Mixed Salt Ketogenic Compositions

The administration of BHB results in elevated and sustained blood levelsof ketone bodies, thereby exploiting the metabolic and physiologicaladvantages of sustained ketosis. Raising the levels of ketone bodies inthe blood provides a subject with greater flexibility in diet options ascompared to a method that aims to induce and sustain ketosis based ondiet alone (e.g., based on fasting and/or limited carbohydrate intake).For example, a subject that has been administered an appropriate amountof BHB will be able to eat an occasional carbohydrate or sugar-basedfood without jeopardizing the ketogenic state and shifting back into aglucose-based metabolic state. Further, such administration facilitateseasier transitioning into a ketogenic state while reducing oreliminating the detrimental effects typically associated with enteringketosis.

Subjects entering or maintaining a ketogenic state will often be in astate of electrolyte imbalance due to the metabolic shifts involved withketosis, including enhanced diuretic effects and changes in insulinprofiles. Thus, while there are many benefits to the administration ofBHB in order to promote or sustain ketosis in a subject, the resultingelectrolyte imbalance, and its associated detrimental physiologicaleffects can offset the benefits of ketosis and/or make it more difficultfor a subject to maintain ketosis at the desired levels or for a desiredlength of time.

Further, because BHB may typically be administered in salt form, whereone or more BHB molecules are the anions to a selected cation, theintroduction of additional cation electrolytes can exacerbate theelectrolyte imbalance of the subject. For example, a formulation havingan overly high level and/or an overly high proportion of a particularform of BHB salt can cause further electrolyte imbalance and/or causeother detrimental health effects. In some circumstances, even if theparticular form of BHB salt eases an electrolyte imbalance to somedegree, it can introduce other negative and undesirable health effects.

By way of example, a formulation having an overly high level and/or anoverly high proportion of sodium BHB compounds will increase levels ofsodium in the subject. While sodium is a necessary nutrient, havinglevels that are outside of optimal ranges can lead to detrimentaleffects. High levels of sodium are associated with hypertension and poorcardiovascular health. In particular, high levels of sodium relative topotassium will promote hypertension and raise the risk of cardiovasculardisease.

In another example, a formulation having an overly high level or anoverly high proportion of calcium BHB salts will increase calcium levelsin the subject. While calcium is also a necessary nutrient, and isparticularly important for good bone health, overly high levels ofcalcium may not be fully absorbed into the bones, and may instead buildup in soft tissues, leading to detrimental calcification and hardeningof the tissues and raising the risk of heart disease (e.g., associatedwith hardened arteries), kidney stones, arthritis, and other problematicconditions. In particular, high levels of calcium relative to magnesiumcan aggravate these negative effects. Magnesium functions by stimulatingthe hormone calcitonin and functions to convert vitamin D to its activeform so it can promote calcium absorption in the bones as opposed tocalcium deposition in soft tissues.

The administration of BHB salts in inappropriate amounts and proportionscan therefore cause or aggravate detrimental health effects. Further,accounting for imbalances through other dietary options is not alwayseasy or even possible for a subject attempting to maintain a ketogenicstate. For example, many of the foods known to have high levels ofpotassium and/or magnesium, such as whole grains, bananas, avocados,milk, yogurt, oatmeal, corn, peas, potatoes, and squash, contain highlevels of carbohydrates and are not compatible with a strict ketogenicdiet when consumed in any substantial amount.

Embodiments disclosed herein provide a therapeutically effective amountof BHB in the form of a mixed BHB salt. Beneficially, the mixed BHB saltis formulated to provide a biologically balanced set of cationelectrolytes. One or more embodiments therefore provide the advantagesof initiating and/or sustaining ketosis while simultaneously promotingpositive electrolytic effects. For example, embodiments disclosed hereinare capable of promoting ketogenesis without aggravating negativeelectrolyte imbalances, without promoting other detrimental healtheffects associated with electrolyte imbalances, and in at least somecircumstances, even improving or easing electrolyte imbalances.

In some embodiments, a ketogenic composition includes a BHB mixed salt.The mixed salt includes at least four different cations, and the mixedsalt is proportioned such that it comprises 10-70% by weight of each ofsodium BHB, potassium BHB, calcium BHB, and magnesium BHB.

In some embodiments, the sodium BHB is included in an amount rangingfrom about 10% to about 30%, or about 12% to about 25%, or about 14% toabout 22%, or about 16% to about 20%, or about 18%, by weight of themixed salt. In some embodiments, the potassium BHB is included in anamount ranging from about 10% to about 30%, or about 12% to about 25%,or about 14% to about 22%, or about 16% to about 20%, or about 18%, byweight of the mixed salt.

In some embodiments, the calcium BHB is included in an amount rangingfrom about 10% to about 40%, or about 12% to about 35%, or about 15% toabout 30%, or about 18% to about 25%, or about 20% to about 23%, byweight of the mixed salt. In some embodiments, the magnesium BHB isincluded in an amount ranging from about 10% to about 40%, or about 12%to about 35%, or about 15% to about 30%, or about 18% to about 25%, orabout 20% to about 23%, by weight of the mixed salt.

The BHB compound can be provided as a racemic mixture of enantiomers, orDL-beta hydroxybutyrate, which can be made synthetically. In humans, theenantiomer D-3-hydroxybutyrate (“D-beta hydrobutyrate” or “D-BHB”) issynthesized in the liver from acetoacetate, the first ketone produced inthe fasting. Therefore, it may be desirable to provide BHB as theenantiomer D-3-hydroxybutyrate to increase potency, either enrichedrelative to L-3-hydroxybutyrate (“L-beta hydrobutyrate” or “L-BHB”) orisolated from L-3-hydroxybutyrate. D-3-hydroxybutyrate is also referredto as “R-beta-hydroxybutyrate”.

In some embodiments, a ketogenic composition additionally includes atherapeutically effective amount of vitamin D₃. Vitamin D₃ works inconjunction with magnesium and calcium to promote good bone health andto prevent undesirable calcification of soft tissues. In preferredembodiments, vitamin D₃ is included in an amount such that an averagedaily dose of the ketogenic composition includes about 200 IU(“International Units”) to about 8000 IU, or about 400 IU to about 4000IU, or about 600 IU to about 3000 IU of vitamin D₃. In some embodiments,vitamin D₃ is included in an amount such that an average daily dose ofthe ketogenic composition includes about 5 μg to about 200 μg, or about10 μg to about 100 μg, or about 15 μg to about 75 μg of vitamin D₃.

Some embodiments include additional BHB salts as part of the mixed saltof the ketogenic composition. For example, some embodiments include oneor more transition metal BHB salts. Transition metal cations suitablefor use as part of the mixed BHB salt include lithium, chromium,manganese, cobalt, copper, zinc, iron, (e.g., as an iron II or iron IIIcation), molybdenum, and selenium.

In embodiments where a transition metal BHB salt is included, preferredsalts include zinc BHB and iron BHB. Some embodiments include a zinc BHBsalt in an amount ranging from about 2% to about 40%, or about 3% toabout 30%, or about 4% to about 20%, or about 5% to about 15%, or about7% to about 13%, by weight of the mixed salt. Some embodiments includean iron BHB salt in an amount ranging from about 2% to about 40%, orabout 3% to about 30%, or about 4% to about 20%, or about 5% to about15%, or about 7% to about 13%, by weight of the mixed salt.

In preferred embodiments, the sodium BHB is included in an amount, byweight, no greater than the amount of the potassium BHB. This canadvantageously enable the administration of necessary sodium andpotassium electrolytes, providing a beneficial electrolytic effect tothe subject, without causing or aggravating any of the unwanted healtheffects associated with high sodium to potassium ratios (e.g.,hypertension, cardiovascular disease, and other unfavorable effects).

In preferred embodiments, the calcium BHB is included in an amount, byweight, no greater than the amount of the magnesium BHB. This canadvantageously enable the administration of necessary calcium andmagnesium electrolytes, providing a beneficial electrolytic effect tothe subject, without causing or aggravating any of the unwanted healtheffects associated with high calcium to magnesium ratios (e.g., tissuecalcification, poor bone health, and other unfavorable effects).

In preferred embodiments, mixed salts can also be formulated such thatthe molar ratio of sodium ions to potassium ions is no greater than 1,and/or such that the molar ratio of calcium ions to magnesium ions in nogreater than 1.

The mixed salt is preferably formulated so that an average daily dose ofthe ketogenic composition provides an amount of at least one of thecations of the mixed salt that is within a range of about 0.25 to about10 times the recommended dietary allowance (RDA) of the of the at leastone cation, or about 0.5 to 5 times, or about 0.75 to 2 times the RDA ofthe at least one cation. For example, the mixed salt may be formulatedsuch that when a subject takes a daily amount of the ketogeniccomposition, the subject will have consumed, through the mixed salt, anamount of the cation electrolyte falling within the foregoing ranges. Insome embodiments, the mixed salt is formulated such that the at leastone cation electrolyte falling within the foregoing ranges after a dailydose of the ketogenic compound is potassium and/or magnesium.

Of course, in some circumstances RDA levels may be exceeded withoutnecessarily experiencing toxicity or negative health effects. One ofskill in the art will understand that in some circumstances, the mixedsalt may be formulated such that one or more of the electrolytes isincluded in an amount that leads to an exceedance of the RDA by morethan 10 times the RDA, without necessarily causing detrimental effects.

In alternative embodiments, BHB compositions may include one or more BHBsalts in which at least some of the cations are provided by one or moreamino acids or other organic compounds that have a net positive chargeat the pH at which the BHB salts are produced. BHB-amino acid salts canprovide soluble forms of BHB without providing electrolytes, such assodium, potassium, calcium or magnesium. This permits the manufacture ofBHB salts with a reduced quantity of electrolytes and/or a more healthyamount and/or healthier balance of electrolytes, particularly where itis desired to delivered higher quantities of BHB for therapeutic reasonswithout further increasing electrolyte load. Suitable amino acids forthis purpose can include amino acids that contain more than one aminegroup capable of being protonated to form a compound having a netpositive charge, which can provide the counter cation for BHB anion.Examples include arginine, lysine, leucine, iso-leucine, histidine,ornithine, citrulline, L-glutamine, or other suitable amino acids ormetabolites of amino acids (e.g., creatine). Some amino acids alsoprovide health benefits. For example, l-arginine can increase nitricoxide in the blood, which dilates blood vessels and improves bloodcirculation for persons with heart conditions (and may help mensuffering from erectile dysfunction).

In some embodiments, a ketogenic composition may also include otherketone body precursors, such as one or more medium chain fatty acids orone or more mono-, di-, or triglycerides of one or more medium chainfatty acids. Including one or more medium chain fatty acids, or a mono-,di-, or triglyceride of one or more medium chain fatty acids can providean additional source for the production of ketone bodies independent ofthe BHB-salts. In other words, the BHB salts promote fast achievement ofketosis in the body while the medium chain fatty acid or a mono-, di-,or triglyceride of a medium chain fatty acid helps sustain the body in astate of ketosis when the BHB salts have already been consumed by thebody. Including at least one of an MCT, medium chain fatty acid, or amono-, di-, or triglyceride of a medium chain fatty acid can helpsustain ketosis over a longer period of time without having to providemore BHB-salts, which can be particularly beneficial when the amount ofBHB salts otherwise required for extended ketosis contain too high of aquantity of electrolytes. The at least one medium chain fatty acidpreferably has from 6 to 12 carbons, more preferably from 8 to 10carbons. Compositions and methods related to the combination of BHB witha medium chain fatty acid, or ester thereof, are disclosed in U.S. Pat.No. 9,138,420, which patent is incorporated herein by this reference inits entirety.

Examples and sources of the medium chain fatty acid, or an ester thereofsuch as a medium chain triglyceride, include coconut oil, coconut milkpowder, fractionated coconut oil, palm oil, palm kernel oil, isolatedmedium chain fatty acids, such as isolated hexanoic acid (i.e, caproicacid), isolated octanoic acid (i.e., caprylic acid), isolated decanoicacid (i.e., capric acid), and lauric acid, medium chain triglycerideseither purified or in natural form such as coconut oil, and esterderivatives of the medium chain fatty acids ethoxylated triglyceride,enone triglyceride derivatives, aldehyde triglyceride derivatives,monoglyceride derivatives, diglyceride derivatives, and triglyceridederivatives, and salts of the medium chain triglycerides. Esterderivatives optionally include alkyl ester derivatives, such as methyl,ethyl, propyl, butyl, hexyl, etc.

As discussed elsewhere, the compositions may also include short chainfatty acids, such as butyric acid, isobutyric acid, valeric acid,isovaleric acid, propionic acid, lactic acid, acetic acid, and the like.

Notwithstanding the foregoing, there is a practical limit to how muchMCT or other medium chain fatty acid source an individual can take, withsome individuals having lower tolerance for MCT or other medium chainfatty acid sources (e.g., they may cause gastrointestinal issues). Theability of the mixed BHB salts to provide a substantial increase in theamount of BHB delivered without providing excessive electrolyte loading,particularly excessive loading of certain electrolytes that are nothealthy in high dosages, such as sodium and calcium ions, permits aperson to sustain a high level of ketosis for a longer period of timewithout having to also consume an excessive quantity of MCT or othermedium chain fatty acid source.

Some embodiments also include one or more additional ketone precursorsor supplements. These additional ketone precursors or supplements mightinclude acetoacetate, ketone esters, and/or other compounds that cause arise in blood ketone levels without adding more electrolytes to thebloodstream.

In some embodiments, the ketogenic composition may be provided as asolid or powder form as opposed to a liquid or gel form. Such solid-formketogenic compositions, in addition to promoting beneficial ketogeniceffects and electrolytic effects described herein, are formulated so asto provide for sufficient ease of handling and manufacturability. Forexample, in a mixed salt formulation of various BUB salts, certain BHBsalts will exhibit different material properties (e.g., hygroscopicity)and the relative amounts of the different salts in the mixed saltformulation will therefore affect the overall properties of thecomposition.

In an alternative embodiment, the ketogenic composition may be providedas a liquid, such as in the form of a shot or mouth spray for fastdelivery and absorption. Liquid forms may include one or more liquidcarriers, such as water, ethanol, glycerin, propylene glycol,1,3-propandiol, and the like, into which the mixed BHB salts aredissolved or dispersed. The composition may include flavoring agentsthat help mask the otherwise poor taste of BHB salts. These includeessential oils, such as peppermint, natural and artificial sweeteners,and other flavorants known in the art.

Manufacturing of the mixed salt formulations described herein hasdemonstrated that certain BHB salts, in particular potassium BHB andmagnesium BHB, exhibit greater hygroscopicity than other BHB salts.Improperly proportioning the BHB salts has been shown to create “sticky”formulations that do not flow or handle well, increasing manufacturingcosts and potentially decreasing the shelf-life, stability and efficacyof the ketogenic composition product.

Accordingly, one or more of the compositions described herein areformulated and balanced so as to provide the ketogenic and electrolyticbenefits and advantages described above, while at the same time notunduly or unacceptably resulting in material properties that overlyhamper or disrupt manufacturability of the salt. In particular, at leastsome embodiments include different BHB salts in proportions that providesufficient calcium BHB and sodium BHB (which typically promotemanufacturability and handling) without overly including these salts atoverly high levels which promote harmful health effects. Likewise, atleast some embodiments include potassium BHB and magnesium BHB (whichtypically hampers manufacturability and handling) in amounts sufficientto balance the calcium BHB but not in overly excessive amounts, whichunduly increases manufacturing difficulty.

In some embodiments, ketogenic compositions may further include one ormore additional components configured to lower the hygroscopicity of thecomposition. For example, various anticaking agents, flow agents, and/ormoisture absorbers, in types and amounts that are safe for consumption,may be included. Such additional components may include one or more ofan aluminosilicate, ferrocyanide, carbonate or bicarbonate salt,silicate (e.g., sodium or calcium silicate), phosphate salt (e.g.,tricalcium phosphate), talcum, powdered cellulose, and the like.

III. Administration

Ketogenic compositions described herein may be administered to a subjectin therapeutically effective dosages and/or in frequencies to induce orsustain ketosis. In some embodiments, a single dose will include anamount of BHB mixed salt ranging from about 1 to about 50 grams, orabout 2 to about 40 grams, or about 5 to about 30 grams, or about 10 toabout 20 grams.

In some embodiments, the ketogenic compositions can include or beadministered together with other supplements, such as vitamin D₃.

In some embodiments, the ketogenic compositions can include or beadministered together with other supplements, such as vitamin D₃.

In some embodiments, the compositions may further include one or moremedium chain fatty acids, fatty acid esters, or mono-, di- ortriglycerides of medium chain fatty acids in order to provide anadditional source of ketone bodies, as discussed elsewhere, forsustaining ketosis for a longer period of time compared to if just theBHB salts were used by themselves. In some embodiments, the compositionis preferably administered such that the ratio of BHB to medium chainfatty acid (or ester thereof) ranges from about 4:1 to about 1:4, orfrom about 2:1 to about 1:2, or from about 1.5:1 to about 1:1.5.

In some embodiments, the subject preferably follows a ketogenic dietthat restricts intake of carbohydrates and protein during the period ofadministration of the composition. In one example embodiment, thesubject may restrict the dietary intake to a ratio of about 65% fat,about 25% protein, and about 10% carbohydrates. The resultingtherapeutic ketosis provides a rapid and sustained keto-adaptation as ametabolic therapy for a wide range of metabolic disorders, and providesnutritional support for therapeutic fasting, weight loss, andperformance enhancement. As such, the composition is typicallyadministered once per day, twice per day, or three times per day to asubject desiring to promote and/or sustain a state of ketosis.

In a preferred embodiment, a ketogenic composition is administered viaoral administration of the composition in a solid and/or powdered form,such as in a powdered mixture (e.g., powder filled gelatin capsules),hard-pressed tablets, or other oral administration route known to thoseskilled in the art.

In some embodiments, multiple doses of the composition are administered.The frequency of administration of the composition can vary depending onany of a variety of factors, such as timing of treatment from previoustreatments, objectives of the treatment, and the like. The duration ofadministration of the composition (e.g., the period of time over whichthe agent is administered), can vary depending on any of a variety offactors, including subject response, desired effect of treatment, etc.

The amount of the composition to be administered can vary according tofactors such as the degree of susceptibility of the individual, the age,sex, and weight of the individual, idiosyncratic responses of theindividual, and the like. The “therapeutically effective amount” is thatamount necessary to promote a therapeutically effective result in vivo(i.e., therapeutic ketosis). In accordance with the present disclosure,a suitable single dose size is a dose that is capable of preventing oralleviating (reducing or eliminating) a symptom in a patient whenadministered one or more times over a suitable time period.

The amount of composition administered will depend on potency,absorption, distribution, metabolism, and excretion rates of the BHBsalts and/or corresponding electrolytes, the method of administration,and the particular disorder being treated, as well as other factorsknown to those of skill in the art. The dose should be sufficient toaffect a desirable response, such as a therapeutic or prophylacticresponse against a particular disorder or condition, taking into accountthe severity of the condition to be alleviated. The compounds may beadministered once, or may be divided and administered over intervals oftime. It is to be understood that administration may be adjustedaccording to individual need and professional judgment of a personadministrating or supervising the administration of the compositions.

IV. Examples

The following is a description of exemplary BHB mixed salt compositionsand other ketogenic compositions useful for inducing and/or sustaining aketogenic state in a subject to which they are administered whilesimultaneously providing a balanced set of cationic electrolytes.

EXAMPLE 1

A BHB mixed salt is prepared by mixing sodium BHB at 23% by weight,potassium BHB at 23% by weight, calcium BHB at 27% by weight, andmagnesium BHB at 27% by weight. The BHB mixed salt is readilyadministered as a ketogenic composition, such as in powder form as adietary supplement mixed with food or drink, in the form of one or morecapsules or tablets, or in liquid form such as a mouth spray.

EXAMPLE 2

A BHB mixed salt is prepared by mixing sodium BHB at 18% by weight,potassium BHB at 18% by weight, calcium BHB at 32% by weight, andmagnesium BHB at 32% by weight. The BHB mixed salt is readilyadministered as a ketogenic composition, such as in powder form as adietary supplement mixed with food or drink, in the form of one or morecapsules or tablets, or in liquid form such as a mouth spray.

EXAMPLE 3

A BHB mixed salt is prepared by mixing sodium BHB at 15% by weight,potassium BHB at 20% by weight, calcium BHB at 30% by weight, andmagnesium BHB at 35% by weight. Vitamin D₃ is added in an amount of 800IU for every 20 grams of the BHB mixed salt (representing an averagedaily dose). The BHB mixed salt is readily administered as a ketogeniccomposition, such as in powder form as a dietary supplement mixed withfood or drink, in the form of one or more capsules or tablets, or inliquid form such as a mouth spray.

EXAMPLE 4

A BHB mixed salt is prepared by mixing sodium BHB at 15% by weight,potassium BHB at 15% by weight, calcium BHB at 35% by weight, andmagnesium BHB at 35% by weight. The BHB mixed salt is readilyadministered as a ketogenic composition, such as in powder form as adietary supplement mixed with food or drink, in the form of one or morecapsules or tablets, or in liquid form such as a mouth spray.

EXAMPLE 5

A BHB mixed salt is prepared by mixing sodium BHB at 30% by weight,potassium BHB at 30% by weight, calcium BHB at 20% by weight, andmagnesium BHB at 20% by weight. Vitamin D₃ is added in an amount of 1200IU for every 15 grams of the BHB mixed salt (representing an averagedaily dose). The BHB mixed salt is readily administered as a ketogeniccomposition, such as in powder form as a dietary supplement mixed withfood or drink, in the form of one or more capsules or tablets, or inliquid form such as a mouth spray.

EXAMPLE 6

A BHB mixed salt is prepared by mixing sodium BHB at 15% by weight,potassium BHB at 15% by weight, calcium BHB at 18% by weight, magnesiumBHB at 18% by weight, zinc BHB at 17% by weight, and iron BHB at 17% byweight. The BHB mixed salt is readily administered as a ketogeniccomposition, such as in powder form as a dietary supplement mixed withfood or drink, in the form of one or more capsules or tablets, or inliquid form such as a mouth spray.

EXAMPLE 7

A BHB mixed salt is prepared by mixing sodium BHB at 20% by weight,potassium BHB at 20% by weight, calcium BHB at 20% by weight, magnesiumBHB at 20% by weight, and zinc BHB at 20% by weight. The BHB mixed saltis readily administered as a ketogenic composition, such as in powderform as a dietary supplement mixed with food or drink, in the form ofone or more capsules or tablets, or in liquid form such as a mouthspray.

EXAMPLE 8

A BHB mixed salt is prepared by mixing sodium BHB at 15% by weight,potassium BHB at 25% by weight, calcium BHB at 20% by weight, magnesiumBHB at 25% by weight, and iron BHB at 15% by weight. The BHB mixed saltis readily administered as a ketogenic composition, such as in powderform as a dietary supplement mixed with food or drink, in the form ofone or more capsules or tablets, or in liquid form such as a mouthspray.

EXAMPLE 9

A BHB mixed salt is prepared by mixing sodium BHB at 15% by weight,potassium BHB at 15% by weight, calcium BHB at 20% by weight, magnesiumBHB at 20% by weight, zinc BHB at 20% by weight, and iron BHB at 10% byweight. Vitamin D₃ is added in an amount of 600 IU for every 10 grams ofthe BHB mixed salt (representing an average daily dose). The BHB mixedsalt is readily administered as a ketogenic composition, such as inpowder form as a dietary supplement mixed with food or drink, in theform of one or more capsules or tablets, or in liquid form such as amouth spray or shot.

EXAMPLE 10

A BHB mixed salt is prepared by mixing sodium BHB at 23% by weight,potassium BHB at 23% by weight, calcium BHB at 27% by weight, andmagnesium BHB at 27% by weight. The BHB mixed salt is readilyadministered as a ketogenic composition, such as in powder form as adietary supplement mixed with food or drink, in the form of one or morecapsules or tablets, or in liquid form such as a mouth spray.

EXAMPLE 11

A BHB mixed salt is prepared by mixing sodium BHB at 25% by weight,potassium BHB at 25% by weight, calcium BHB at 25% by weight, andmagnesium BHB at 25% by weight. The BHB mixed salt is then mixed with ananti-caking agent, which is safe for human consumption, at a ratio of 4to 1 to form a ketogenic composition readily administered to a subject,such as in powder form as a dietary supplement mixed with food or drink,or in the form of one or more capsules or tablets.

EXAMPLE 12

Any of the foregoing BHB mixed salts is combined with at least onemedium chain fatty acid source selected from a medium chaintriglyceride, medium chain fatty acid, monoglyceride of a medium chainfatty acid, diglyceride of a medium chain fatty acid, or triglyceride ofa medium chain fatty acid having 8 to 10 carbons to provide a ketogeniccomposition that provides prolonged ketosis over a greater period oftime than would be provided by a given dosage of BHB mixed salt byitself. The ratio of medium chain fatty acid source to BHB salts is 4:1,3:1, 2:1, 1:1 or 1:2.

EXAMPLE 13

Any of the foregoing BHB mixed salts includes one or more BHB salts of acationic amino acid selected from arginine, lysine, leucine,iso-leucine, histidine, ornithine, citrulline, L-glutamine, ormetabolite of an amino acid, such as creatine). The BHB-amino acid saltdecreases the ratio of electrolytes to BHB anions in the composition.

The present invention may be embodied in other specific forms withoutdeparting from its spirit or essential characteristics. The describedembodiments are to be considered in all respects only as illustrativeand not restrictive. The scope of the invention is, therefore, indicatedby the appended claims rather than by the foregoing description. Allchanges which come within the meaning and range of equivalency of theclaims are to be embraced within their scope.

1. A composition for increasing ketone level in a subject, comprising:at least one beta-hydroxybutyrate salt selected from: calciumbeta-hydroxybutyrate; and magnesium beta-hydroxybutyrate; and at leastone other beta-hydroxybutyrate salt selected from: sodiumbeta-hydroxybutyrate; potassium beta-hydroxybutyrate; calciumbeta-hydroxybutyrate; magnesium beta-hydroxybutyrate; and amino acidsalts of beta-hydroxybutyrate, wherein the composition is in solidand/or powder form, wherein the composition is free of medium chainfatty acids having 6 to 12 carbons and glycerides or other estersthereof.
 2. The composition of claim 1, wherein the compositioncomprises calcium beta-hydroxybutyrate and magnesiumbeta-hydroxybutyrate.
 3. The composition of claim 2, wherein thecomposition further comprises sodium beta-hydroxybutyrate.
 4. Thecomposition of claim 2, wherein the composition further comprisespotassium beta-hydroxybutyrate.
 5. The composition of claim 1, whereinthe composition comprises calcium beta-hydroxybutyrate, sodiumbeta-hydroxybutyrate, and potassium beta-hydroxybutyrate.
 6. Thecomposition of claim 1, wherein the composition comprises magnesiumbeta-hydroxybutyrate, sodium beta-hydroxybutyrate, and potassiumbeta-hydroxybutyrate.
 7. The composition of claim 1, wherein thebeta-hydroxybutyrate salts comprise 10% to 70% by weight of calciumbeta-hydroxybutyrate.
 8. The composition of claim 1, wherein thebeta-hydroxybutyrate salts comprise 10% to 70% by weight of magnesiumbeta-hydroxybutyrate.
 9. The composition of claim 1, wherein thebeta-hydroxybutyrate salts comprise 10% to 70% by weight of sodiumbeta-hydroxybutyrate.
 10. The composition of claim 1, wherein thebeta-hydroxybutyrate salts comprise 10% to 70% by weight of potassiumbeta-hydroxybutyrate.
 11. The composition of claim 1, further comprisingat least one of anticaking agent, flow agent, moisture absorber,aluminosilicate, ferrocyanide, carbonate salt, bicarbonate salt,silicate, phosphate, talcum, or powdered cellulose.
 12. The compositionof claim 1, further comprising at least one of acetoacetate, vitamin,lithium, chromium, manganese, cobalt, copper, zinc, iron, molybdenum,selenium, amino acid, flavoring agent, essential oil, natural sweetener,artificial sweetener, or other supplement.
 13. A composition forincreasing ketone level in a subject, comprising: at least onebeta-hydroxybutyrate salt selected from: calcium beta-hydroxybutyrate;and magnesium beta-hydroxybutyrate; and at least one otherbeta-hydroxybutyrate salt selected from: sodium beta-hydroxybutyrate;potassium beta-hydroxybutyrate; calcium beta-hydroxybutyrate; magnesiumbeta-hydroxybutyrate; and amino acid salts of beta-hydroxybutyrate,wherein the composition comprises a greater total weight of calcium andmagnesium beta-hydroxybutyrate salts than a total weight of sodium andpotassium beta-hydroxybutyrate salts, wherein the composition is free ofmedium chain fatty acids having 6 to 12 carbons and glycerides or otheresters thereof.
 14. The composition of claim 13, wherein the compositioncomprises only one of calcium beta-hydroxybutyrate or magnesiumbeta-hydroxybutyrate.
 15. The composition of claim 13, wherein thecomposition comprises only one of sodium beta-hydroxybutyrate orpotassium beta-hydroxybutyrate.
 16. A composition for increasing ketonelevel in a subject, comprising: at least one beta-hydroxybutyrate saltselected from: calcium beta-hydroxybutyrate; and magnesiumbeta-hydroxybutyrate; and at least one other beta-hydroxybutyrate saltselected from: sodium beta-hydroxybutyrate; potassiumbeta-hydroxybutyrate; calcium beta-hydroxybutyrate; magnesiumbeta-hydroxybutyrate; and amino acid salts of beta-hydroxybutyrate,wherein the composition comprises a greater total weight of sodium andpotassium beta-hydroxybutyrate salts than a total weight of calcium andmagnesium beta-hydroxybutyrate salts, wherein the composition is free ofmedium chain fatty acids having 6 to 12 carbons and glycerides or otheresters thereof.
 17. The composition of claim 16, wherein the compositioncomprises only one of sodium beta-hydroxybutyrate or potassiumbeta-hydroxybutyrate.
 18. The composition of claim 16, wherein thecomposition comprises only one of calcium beta-hydroxybutyrate ormagnesium beta-hydroxybutyrate.
 19. A composition for increasing ketonelevel in a subject, comprising: at least one beta-hydroxybutyrate saltselected from: calcium beta-hydroxybutyrate; and magnesiumbeta-hydroxybutyrate; and at least one other beta-hydroxybutyrate saltselected from: sodium beta-hydroxybutyrate; potassiumbeta-hydroxybutyrate; calcium beta-hydroxybutyrate; magnesiumbeta-hydroxybutyrate; and amino acid salts of beta-hydroxybutyrate; andat least one of anticaking agent, flow agent, moisture absorber,aluminosilicate, ferrocyanide, carbonate salt, bicarbonate salt,silicate, phosphate, talcum, or powdered cellulose, wherein thecomposition is free of medium chain fatty acids having 6 to 12 carbonsand glycerides or other esters thereof.
 20. The composition of claim 19,further comprising at least one of acetoacetate, vitamin, lithium,chromium, manganese, cobalt, copper, zinc, iron, molybdenum, selenium,amino acid, flavoring agent, essential oil, natural sweetener,artificial sweetener, or other supplement.